Since the compounds of Formula I have asymmetrical carbon atoms, the optically active forms and racemic mixtures of these compounds are also subject matter of the invention. Since the compounds of Formula I contain groups capable of tautometry, all tautomeric forms of these compounds are also subject matter of the invention.
It is known that 1-amino-3-aryloxy-2-propanol derivatives have a beta-adrenergic blocking activity. In Netherlands Patent No. 68.18289, derivatives are described which have aliphatic moieties R.sub.3 ; German Patent No. 1,493,887 and British Patent No. 1,185,046 claim substances having aliphatic and carboxyclic moieties R.sub.3. One prominent representative of these compounds, practolol, has meantime proved to be toxic and has had to be withdrawn from the market.
Compounds having heterocyclic moieties R.sub.3 have never previously become known. The use of these moieties produces a surprising intensification of action, and brings it about that the substances thus far have shown no practolol-like toxicity.
The term, "a low alkyl group" of the substituents R.sub.1, R.sub.3 and R.sub.5, as used herein, is to be understood to refer to straight-chain or branched groups having one to six, preferably one to four carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert. butyl or n-hexyl.
Alkanoyl groups of substituents R.sub.2 and R.sub.4 contain one to eight, preferably one to five carbon atoms, and their alkyl groups can be straight-chain, branched or cyclic. The acetyl moiety and the pivaloyl moiety are preferred.
The term, "aroyl group" of substituent R.sub.4, is to be understood to refer to a benzoyl or a naphthoyl group.
Alkoxy groups of substituents R.sub.3 and R.sub.5 contain one to six, preferably one to four carbon atoms, examples being the methoxy, ethoxy, propoxy, butoxy or pentoxy group. The methoxy, ethoxy and propoxy groups are preferred.
Halogen, in the meaning of the invention, is to be understood to refer to fluorine, chlorine, bromine and iodine, especially fluorine, chlorine and bromine.
The term, "heterocyclic moieties" of substituents R.sub.3 and R.sub.5, is to be understood to mean monocyclic and bicyclic compounds consisting of five- and/or six-member rings having one or two hetero atoms. Nitrogen, oxygen and sulfur can be the hetero atoms. The heteroxyclics can be unsaturated, saturated or partially unsaturated. The pyrrolyl, pyrrolinyl, pyridyl, pyrazinyl, thiazolyl, indolyl, tetrahydroindolyl, quinolinyl, benzofuranyl and benzimidazolyl moieties are preferred.
Carbocyclic aryl moieties can be phenyl or naphthyl moieties, the phenyl moiety being especially preferred.
The preparation of the new compounds of the general Formula I is characterized either by reacting, in a known manner,
(a) a compound of Formula II ##STR2## wherein R.sub.1, R.sub.2 and R.sub.4 have the meaning given above, and Q represents hydrogen or a protective group with a compound of Formula III EQU Y--CO--X--R.sub.3 (III),
wherein X and R.sub.3 have the meaning given above and Y represents a reactive moiety, or
(b) by reacting a compound of Formula IV ##STR3## wherein R.sub.2, R.sub.3 and X have the same meaning as above, B represents a reactive group, and R.sub.4 ' has the same meaning as R.sub.4 or together with B represents a valence line, with a compound of Formula V EQU R.sub.1 NH-Q (V),
wherein R.sub.1 and Q have the meaning given above, or
(c) by reacting a compound of Formula VI ##STR4## wherein R.sub.2, R.sub.3 and X have the same meaning as above, with a compound of Formula VII ##STR5## wherein
R.sub.1 has the same meaning as above,
B' represents a reactive group,
D represents a CO- or CH-OR.sub.4 " group, R.sub.4 " having the same meaning as R.sub.4 given above or representing together with B' a valence line, and
Q' has the same meaning given above for Q or, together with B', can be a single bond, and, if D represents the CO group, then reducing the product, splitting off, if desired, a protective group representing Q or Q', transforming afterwards, if desired, one moiety R.sub.4 in a product compound of the general Formula I, by conventional methods, to another moiety R.sub.4 defined by the claim, and converting the obtained compounds, if desired, to their pharmacologically compatible salts.
Protective groups representing Q or Q' in compounds of Formulas II, V and VII can be moieties which can be split off by hydrolysis or hydrogenolysis, such as for example low alkanoyl, aroyl, arylmethyl, diarylmethyl or triarylmethyl moieties. The benzyl moiety is preferred.
Reactive moieties Y in compounds of the general Formula III can be any moieties which are used in peptide chemistry for the activation of carboxylic acids, such as for example halogen atoms, the azido group, alkyloxy groups, aryloxy groups and acyloxy groups.
Reactive groups B in compounds of the general formula IV, and B' in compounds of general formula VII, are especially acid moieties, for example those of hydrogen halide acids and sulfonic acids. Chlorides, mesyloxy and tosyloxy moieties are especially preferred.
The methods of the invention are best performed in a solvent that is inert under the conditions of the reaction, such as water, methanol, ethanol, n-butanol, dioxane, dimethylformamide, hexamethylphosphoric acid triamide, or ethylene glycol dimethyl ether, in the presence, if desired, of an acid-binding agent. The reactions can also be achieved by mixing the components of the reaction without solvent. The reactions are performed at room temperature or with heating, under a protective gas atmosphere if necessary.
The reduction of the group CO representing D, if it is to be performed, is best carried out by catalytic hydrogenation with noble metal or nickel catalysts, or by means of complex metal hydrides such as sodium borohydride.
The starting compounds used in the method of the invention are, as a rule, compounds known in the literature. New compounds are generally obtained in a manner similar to the method described for the preparation of these known compounds.
An example of a transformation of a substituent R.sub.4, to be performed after the principal reaction in some cases, is the acylation of an OH group to an alkanoyloxy or aroyloxy group. The esterification can be accomplished in a conventional manner by reaction with an acid halide or acid anhydride, in the presence, if desired, of an acid-binding agent such as pyridine or triethylamine, for example.
The splitting off of an arylmethyl, diarylmethyl or triarylmethyl group representing Q or Q' is performed, for example by hydrogenation in the presence of noble metal catalysts.
For the conversion of the compounds of Formula I to their pharmacologically acceptable salts, they are reacted, preferably in an organic solvent, with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, lactic acid, citric acid, maleic acid or benzoic acid.
The compounds of Formula I pursuant to the invention can be produced in the form of a racemic mixture. The separation of the racemate into the optically active forms is accomplished through the diastereomeric salts, by methods known in themselves. Tartaric acid, malic acid, camphoric acid and camphorsulfonic acid can chiefly be used as active acids.
For the preparation of pharmaceutical products, the compounds of Formula I are mixed in a known manner with suitable pharmaceutical vehicles, flavoring agents, aromatic substances and dyes, and formed, for example, into tablets or dragees, or they are suspended or dissolved in water or oil, such as olive oil, with the addition of appropriate adjuvants.
The new compounds of Formula I pursuant to the invention and their salts can be administered enterally or parenterally in liquid or solid form. As the medium for injectables, water is used preferentially, and contains the additives commonly used in injectable solutions, such as stabilizers, solubilizers or buffers. Examples of such additives are tartrate and citrate buffers, ethanol, complexing agents (such as ethylene diamine tetraacetic acid and its non-toxic salts), and polymers of high molecular weight (such as liquid polyethylene oxide) to control viscosity. Examples of solid vehicles are starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicic acids, fatty acids of higher molecular weight (such as stearic acid), gelatines, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high polymers (such as polyethylene glycols); preparations suitable for oral administration can contain flavoring agents and sweeteners, if desired.
The dosage used will depend on the age, state of health and body weight of the patient, the severity of the illness, other treatment simultaneously administered, the frequency of the treatments, and the kind of action desired. Usually the daily dose of the active compounds amounts to from 0.1 to 50 milligrams per kilogram of body weight. Normally, 0.5 to 40, and preferably 1.0 to 20 mg/kg/day in one or more doses per day are effective in obtaining the desired results.
The following experiments were performed for the detection of the beta-adrenergic blocking activity: